1. Field of the Invention
The invention concerns 1.4;3.6-dianhydrohexitol nitrates substituted by purine bases, namely, adenyldesoxy-1.4;3.6-dianhydrohexitol nitrates of the general formula Ia, ##STR2## as well as theophyllinyldesoxy-1.4;3.6-dianhydrohexitol nitrates of the general formula Ib: ##STR3##
2. Description of the Prior Art
The basic structure of these compounds consists of one of the stereoisomeric 1.4;3.6-dianhydrohexitols convertible into one another by epimerisation, namely, either 1.4;3.6-dianhydro-L-iditol (="isoidide") (II), ##STR4## in which the OH groups in the 2- and 5-position each have the exo-configuration, or 1.4;3.6-dianhydro-D-glucitol (="isosorbide") (III) ##STR5## which has an exo-standing and an endo-standing OH group and thus--in the case of various substituents in the 2- and 5-position--occurs in two isomeric forms.
Finally, the basic structure of some intermediate products consists of 1.4;3.6-dianhydro-D-mannitol (="isomannide") (IV), ##STR6## which has two endo-standing OH groups.
Since, in contradistinction to the glucitol derivatives, in the case of the iditol and mannitol derivatives a difference between the 2- and 5-substituents is not possible because the C.sup.2 atom, in the case of rotation of the molecule through 180.degree., becomes the C.sup.5 atom, references to the 5-position or 2-position of substituents is, in the case of these derivatives, superfluous. However, for a better comparison of the structures of the individual compounds with the general formulae, the isoidide derivatives are here all referred to as 5-purinylisoidide derivatives since they result from isosorbide derivatives acyl substituted in the 5-position. Correspondingly, the isomannide acyl derivatives used as starting compounds are referred to as 2-acylisomannide derivatives since the 2-purinylisosorbide derivatives are prepared from them.
A brief summary of the stereoisomerism of the 1.4;3.6-dianhydrohexitols is given by J. A. Mills in Advances in Carbohydrate Chem., 10, 1-53 (1955).
Furthermore, the invention is concerned with processes for the preparation of the initially mentioned 1.4;3.6-dianhydrohexitol mononitrates substituted by purine bases, as well as pharmaceutical compositions which contain the compounds according to the invention.
The nitrates of 1.4;3.6-dianhydro-D-glucitol (also called 1.4;3.6-dianhydro-D-sorbitol) are known e.g. from U.S. Pat. No. 3,886,186, namely, not only in the 2- and 5-mononitrates but also the 2,5-dinitrates of isosorbide. These nitrates, especially the dinitrate, which is already commercially available as a medicament, are pharmacologically-active substances with haemodynamic, vasodilatory and antiaginous effectiveness, which are used especially in the case of coronary insufficiency and for the treatment of angina pectoris.
The pharmacokinetics of the dinitrate and of the mononitrates of isosorbide, isomannide and isoidide have been described by Bogaert and Rosseel in Naunyn-Schmiedeberg's Arch. Pharmacol., 275, 339 (1972).
However, it has been shown that the nitrates cause unpleasant side effects, especially headaches. Furthermore, the mononitrates are more poorly resorbed than, for example, isosorbide dinitrate (ISDN). It is also to be added that the dinitrates of isosorbide, isomannide and isoidide can only be prepared and handled with special precautionary measures, since they are explosive.
Thus, there is a need for the making available of new pharmaceutical agents with the same activity spectrum but which do not display the mentioned disadvantages and for the provision of new 1.4;3.6-dianhydrohexitol mononitrates which can be used as active components of such pharmaceutical agents.
The task forming the basis of the invention consists in satisfying the mentioned need, the solution of this problem in the making available of the substances according to the invention.